Your Cholesterol Profile Gary E. Foresman, MD February, 2011

Your Cholesterol Your Cholesterol ProfileProfile

Gary E. Foresman, MDGary E. Foresman, MD

February, 2011February, 2011

Cholesterol MetabolismCholesterol Metabolism1.1. Cholesterol is an alicyclic compound with a Cholesterol is an alicyclic compound with a

structure:structure:

a.a. Perhydrocyclopentanophenanthrene Perhydrocyclopentanophenanthrene nucleus of 4 fused rings nucleus of 4 fused rings (5-cholesten-3B-01)(5-cholesten-3B-01)

Cholesterol MetabolismCholesterol Metabolism

2.2. Low solubility in water: 0.2mg / 100ml at Low solubility in water: 0.2mg / 100ml at 250 C250 C

3.3. Solubility in blood is due to lipoproteins Solubility in blood is due to lipoproteins (LDL, VLDL)(LDL, VLDL)

4.4. Total cholesterolTotal cholesterol

a.a. Free 30%Free 30%

b.b. Cholesterol Esters 70% (FA is Saturated or Cholesterol Esters 70% (FA is Saturated or Unsaturated)Unsaturated)

Long chain FA attached by ester bond to Long chain FA attached by ester bond to OH group on C-3 on the A-ring (usually OH group on C-3 on the A-ring (usually linoleic acid) enhances hydrophobiticity.linoleic acid) enhances hydrophobiticity.


5. Structure:

6. Bile concentration = 390 mg %

7. Cholesterol Functions:A. Plasma and intracellular membranes (Free

Unesterified form)B. Myelinated structures of brain and CNSC. Inner Mitrochrondrial MembraneD. Bile AcidsE. Steroid Hormones and Sex HormonesF. Ergosterol ----- UV Skin --> Vitamin D3

(cholecalciferol)

8. Synthesis is greatest in:– Liver– Intestine– Adrenal Cortex– Reproductive Tissues (Ovary, Testes)


1. Also called mevalonate: NADP+ oxidoreductase (a residentglycoprotein).

2. Requires NADPH as reductant -2 moles (4 E-)3. Hydrolysis of thioester bond of HMG-CoA4. Generates a primary alcohol residue : mevalonate5. Irreversible RX6. Produces (R) – (+) mevalonate with 6 C atoms7. Rate limiting step8. Intrinsic membrane protein of the ER (Endoplasmic

Reticulum) whose carboxyl terminus extends into the cytosol and carries the enzyme’s active site. N-terminus anchors it to ER.

9. Phosphorylation regulates activity by AMP activated protein kinasethat diminishes its catalytic activity

HMG-CoA Reductase HMG-CoA Reductase EnzymeEnzyme

10. Increased intracellular cholesterol stimulates the phosphorylation ofHMGCoA Reductase

11. Most regulated enzyme known in humans: • Concentrations of products of mevalonate pathway

• Cholesterol• Farnesyl Pyrophosphate (FPP)

• Prenylated proteins• 2-cis geranylgeranyl PP (GGPP) Dolichols• All-trans geranylgeranyl (GGPP) Ubiquinone

• Heme• Selenoproteins

HMG-CoA Reductase HMG-CoA Reductase EnzymeEnzyme

The New Gold Standard for Lipoprotein Analysis

Ad

van

ced

Testi

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for

Card

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Ris

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“The Lipid Panel”

Evolution of Lipoprotein Evolution of Lipoprotein TestingTesting

Direct LDL is Better

Total Cholesterol =Total Cholesterol = VLDLVLDL + + LDL LDL + +

HDLHDL

Calculated LDL = TC – (HDL + TG/5)

Friedewald Equation: VLDL = TG/5

Lipoprotein Particle Numbers by Subgroup is Best

Apo B 100 (est. of non-HDL Particles) is Better Yet

Consensus Statement of the American Diabetes Assoc. & American College of Cardiology

Lipoprotein Particles Predict Risk Better than Cholesterol

Separation by Density Separation by Density

Centrifuge Tube with Mixture of Serum, Gradient and Dye

Proteins

LDL

VLDL

HDL

Intense Gravitational Force

Separated Lipoproteins

600,000 G’s

Density (g/ml)

1.030

1.006

1.300

1.000

1.100

1.063

NCEP Guidelines for Cardiovascular NCEP Guidelines for Cardiovascular Disease Disease

NCEP Identified a Number of New Lipoprotein Risk Factors – To Help Assess Those at Risk

NCEP - ATP III

50% of at Risk Individuals are Not Identified

50% of Heart Attack Victims have

Normal Cholesterol

NCEP New Lipoprotein Risk NCEP New Lipoprotein Risk FactorsFactors

Small Dense LDL – - 3-fold Greater Risk of CVD than Buoyant LDL - Penetrates Arterial Endothelial Lining Easily - Less Recognized by LDL Receptors therefore Increases

HDL 2b & 3 –- HDL 3 Picks Up Excess Cholesterol and Becomes HDL 2b in Reverse Cholesterol Transport

Lp(a) -- Small Particles that are Easily Oxidized - Competes with Plasminogen, Prevents Fibrinolysis

RLP (Remnant Lipoprotein) - - One of the Most Atherogenic Lipoproteins - Skips Oxidation Step in Forming Plaque

High in 20% of population



Low in 20% of population

Lp(a) Competes with Plasminogen Lp(a) Competes with Plasminogen and Prevents Fibrinolysisand Prevents Fibrinolysis

Fibrin

Fibrinogen

Blood Clot(MI, Stroke

or DVT)

Fibrinolysis

Plasmin

Plasminogen

Many of the over 40 genetic variations of Lp(a) mimic plasminogen

Lp(a)

Possible Antithrombotic Therapy Indicated

To Determine the NCEP NewTo Determine the NCEP New Risk Factors Risk Factors Lipoprotein Subgroup Lipoprotein Subgroup Information is Needed:Information is Needed:

Advanced Lipoprotein Advanced Lipoprotein TestingTesting

What are Lipoproteins and their Subgroups?

How do they Cause Cardiovascular Disease?

Lipoprotein Lipoprotein Particles Particles

ApolipoproteinA-1 (HDL) or B-

100 (LDL)

Unesterified Cholesterol

Cholesterol Ester

Phospholipid

Triglyceride

Atherogenic Atherogenic ParticlesParticles

Size (nm)Size (nm)

Density (g/ml)Density (g/ml)

VLDLVLDL

1.0041.0045050

TG-rich LipoproteinsTG-rich Lipoproteins

RLPRLP

2525

1.0131.013

BuoyantBuoyant LDLLDL

2222

1.0231.023

DenseDenseLDLLDL

1919

1.0441.044

Mean EndothelialMean EndothelialPore SizePore Size

CETP in Cholesterol CETP in Cholesterol MetabolismMetabolismHL

LDL 1-2

LPLIDL

HL

LDL 3-4

HDL Enters Cells &

Arterial Intima NascentHDL

Apo A-1

Liver

CETPTG’s

CE

VLDL

Apo B-100

Liver

LCAT

HDL3Reverse

Cholesterol Transport

LCAT

HDL2b

Brewer HB et al. Am J Cardiol 2003;92:10K-16K.

HDL REMOVESEXCESS LIPIDS

ARTERIAL INTIMA

MACROPHAGE CELL

FOAMCELLSBUILD

PLAQUE

RLP

Atherosclerotic Plaque Atherosclerotic Plaque FormationFormation

ARTERIAL LUMEN

DENSELDL

Lp(a)

INFLAMMATION RUPTURES PLAQUE

LDL

OXIDIZEDLDL

MONOCYTE CELL

FOAM CELL

Atherogenic Profile

LPP showing NCEP’s New Lipoprotein Risk LPP showing NCEP’s New Lipoprotein Risk FactorsFactors

Atherogenic Profile

High RLP

Dense LDL

Low HDL 2b

Healthy Profile

Buoyant LDL High HDL

2bLow RLP

Treatment of Treatment of DyslipidemiaDyslipidemia






Treatment of DyslipidemiaTreatment of Dyslipidemia

Date

March of 2010

Aug. of 2010

Nov. of 2010Feb. of 2011

Total Cholesterol

258 146 167 188

Triglycerides 164 71 73 233

HDL 44 50 66 44

LDL 181 82 86 97

LDL/HDL 4.1 1.4 1.1 2.2

Trig/HDL 3.7 1.6 1.3 5.3

*Add Lipitor 20mg

and 3g/day Arctic PureEPA/DHA

*Patient switches to

Kirkland Fish Oils







Lipoprotein Therapeutic Statins Niacin Fibrates Estrogens Resins Absorption Omega-3’s Alcohol Life Style Inhibitors EPA & DHA (moderate) Changes (diet & exercise)

VLDL (Triglycerides) ♥ ♥ ♥♥ ♥♥ X X ♥ ♥♥ ■

RLP (IDL) ♥ ♥ ♥ ♥ X X ♥ ♥♥** ■

LDL I & II - buoyant ♥ ♥♥ ♥ ♥ ♥ ♥ ♥ ♥ ** ■

LDL III - dense ♥ ♥** ♥♥ ♥ ♥♥ ♥ ♥ ■ ■

LDL IV or Lp(a) ■ ■ ♥♥ ■ ♥ ■ ■ ■ ■

HDL 2b - buoyant ♥♥ ♥ ♥ ♥ ♥ ■ ■ ■ ♥

HDL 2a & 3 ♥ ♥ ♥♥ ♥ ♥ ■ ■ ■ ♥ _____________________________________________________________________________________________________ _____________

♥♥ Therapeutic ♥ Beneficial ■ Little or No Effect X Negative Result *These guidelines provide some of the treatment options available to modify lipoprotein particle numbers determined by the LPPTM test. **Spectracell Laboratories observed response to treatment. The National Cholesterol Education Program (NCEP) guidelines provide dosage information on the treatment options.

Lipoprotein Particle Lipoprotein Particle Numbers Numbers

Therapeutic GuidelinesTherapeutic Guidelines

Documents

Your Cholesterol Profile Gary E. Foresman, MD February, 2011